Biology subjects

Jarodsky, J. M.

Publications and source records attributed to Jarodsky, J. M..

2 recordsLinked to original sources

bioRxiv2025

Reversible lipid mediated pH-gating of connexin-46/50 by cryo-EM

Gap junctions, formed by connexin proteins, establish direct electrical and metabolic coupling between cells, enabling coordinated tissue responses. These channels universally respond to intracellular pH changes, closing under acidic conditions to limit the spread of cytotoxic signals during cellular stress, such as ischemia. Using cryo-electron microscopy (cryo-EM), we uncover insights into the structural mechanism of pH-gating in native lens connexin-46/50 (Cx46/50) gap junctions. Mild acidification drives lipid infiltration into the channel pore, displacing the N-terminal (NT) domain and stabilizing pore closure. Lipid involvement is both essential and fully reversible, with structural transitions involving an ensemble of gated-states formed through non-cooperative NT domain movement as well as minor populations of a distinct destabilized open-state. These findings provide molecular insights into pH-gating dynamics, illustrating how structural changes may regulate gap junction function under cellular stress and linking Cx46/50 dysregulation to age-related cataract formation.

biophysics↗

bioRxiv2025

Calcium induced N-terminal gating and pore collapse in connexin-46/50 gap junctions

Gap junctions facilitate electrical and metabolic coupling essential for tissue function. Under ischemic conditions (e.g., heart attack or stroke), elevated intracellular calcium (Ca2+) levels uncouple these cell-to-cell communication pathways to protect healthy cells from cytotoxic signals. Using single-particle cryo-EM, we elucidate details of the Ca2+-induced gating mechanism of native connexin-46/50 (Cx46/50) gap junctions. The resolved structures reveal Ca2+ binding sites within the channel pore that alter the chemical environment of the permeation pathway and induce diverse occluded and gated states through N-terminal domain remodeling. Moreover, subunit rearrangements lead to pore collapse, enabling steric blockade by the N-terminal domains, reminiscent of the "iris model" of gating proposed over four decades ago. These findings unify and expand key elements of previous gating models, providing mechanistic insights into how Ca2+ signaling regulates gap junction uncoupling and broader implications for understanding cell stress responses and tissue protection.

biophysics↗